Palladium-catalyzed indolization of N-aroylbenzotriazoles with disubstituted alkynes

Article abstract of DOI:10.1021/ol900113f

The palladium-catalyzed denitrogenative indolization of N-aroylbenzotriazoles 1 and internal alkynes 2 produced the corresponding polysubstituted indoles 3 in good to high yields. For example, the reaction of 5,6-dimethyl-1-[4-(trifluoromethyl)benzoyl]ben

Full text of DOI:10.1021/ol900113f

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1055-1058
Palladium-Catalyzed Indolization of
N-Aroylbenzotriazoles with Disubstituted
Alkynes
Itaru Nakamura,* Tetsuya Nemoto, Naozumi Shiraiwa, and Masahiro Terada
Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
itaru-n@mail.tains.tohoku.ac.jp
Received November 28, 2008
ABSTRACT
The palladium-catalyzed denitrogenative indolization of N-aroylbenzotriazoles 1 and internal alkynes 2 produced the corresponding polysubstituted
indoles 3 in good to high yields. For example, the reaction of 5,6-dimethyl-1-[4-(trifluoromethyl)benzoyl]benzotriazole (1j) with 6-dodecyne (2a),
4-octyne (2b), and diphenylacetylene (2f) in the presence of 10 mol % of Pd(PPh3)4 without solvent at 130 °C gave the corresponding indoles
3i, 3l, and 3p in 74, 71, and 41% yields, respectively. In the present reaction, the aroylbenzotriazole acts as a synthetic equivalent of a
2-haloanilide in Larock’s indole synthesis.
Indoles have been widely utilized in pharmaceutical and
material sciences. Therefore, the efficient construction of
indole derivatives in organic synthesis is of great impor-
tance.1 One of the most powerful synthetic methods to make
these compounds is the palladium-catalyzed cyclization of
2-haloanilines with alkynes. This is generally recognized as
Larock’s indole synthesis2 and has been widely utilized for
the synthesis of indole-containing biologically active com-
pounds (Scheme 1).3 This method, however, still suffers from
Scheme 1. Larock’s Indole Synthesis
(1) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (b)
Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (c) Campo, J.; Garc´ıa-
Valverde, M.; Marcaccini, S.; Rojo, M. J.; Torroba, T. Org. Biomol. Chem.
2006, 4, 757. (d) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106,
2875.
(2) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652. (c) Ku¨rti, L.; Czako´, B. Strategic Applications of Named Reactions
in Organic Synthesis; Elsevier, Inc.: New York, 2005; pp 260. (d) Leogane,
O.; Lebel, H. Angew. Chem., Int. Ed. 2008, 47, 350.
the viewpoint of atom efficiency. That is, the formation of
stoichiometric amounts of halogenoic acid derived from
2-haloanilines as byproducts is unavoidable, and therefore,
an excess (2-5 equiv) of base has to be used in order to
capture the halogenoic acid. We envisioned the use of
N-acylbenzotriazoles to replace 2-haloanilides in palladium-
catalyzed reactions by combining two concepts, that is,
thermal isomerization of the benzotriazole to the correspond-
ing 2-iminobenzenediazonium species A4,5 and oxidative
(3) (a) Farr, R. N.; Alabaster, R. J.; Chung, J. Y. L.; Craig, B.; Edwards,
J. S.; Gibson, A. W.; Ho, G.-J.; Humphrey, G. R.; Johnson, S. A.;
Grabowski, E. J. J. Tetrahedron: Asymmetry 2003, 14, 3503. (b) Lanter,
J. C.; Fiordeliso, J. J.; Jiang, W.; Allan, G. F.; Lai, M.-T.; Linton, O.; Hahn,
D. W.; Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. Lett. 2007, 17, 123. (c)
Lee, K. L.; Foley, M. A.; Chen, L.; Behnke, M. L.; Lovering, F. E.;
Kirincich, S. J.; Wang, W.; Shim, J.; Tam, S.; Shen, M. W. H.; Khor, S.;
Xu, X.; Goodwin, D. G.; Ramarao, M. K.; Nickerson-Nutter, C.; Donahue,
F.; Ku, M. S.; Clark, J. D.; McKew, J. C. J. Med. Chem. 2007, 50, 1380.
10.1021/ol900113f CCC: $40.75
Published on Web 02/09/2009
2009 American Chemical Society

+
without solvent at 130 °C for 8 h gave 2,3-dipentyl-1-[4-
(trifluoromethyl)benzoyl]indole 3b in 69% yield (entry 2).8
When acetonitrile was used as the solvent, the yield decreased
to 54%. Other palladium catalyst systems, such as Pd2(dba)3·
CHCl3-PPh3 and Pd(OAc)2-PPh3, were not effective, and the
reaction in the absence of palladium catalysts did not proceed
at all (see the Supporting Information). The reaction at 100 °C
afforded 3b in 10% yield along with 84% of recovered 1b. The
reaction using 1 equiv of 2a gave 3b in 42% yield. The
electronic character of the arylcarbonyl group on the nitrogen
atom of the benzotriazole significantly influenced the reaction.
The yield of 3 increased with the order of the electron-
withdrawing ability of the arylcarbonyl group. However, the
reaction of 1a with 2a gave 3a in a lower yield due to fast
decomposition of 1a under the reaction conditions (entries 1-6).
In contrast, the reaction of 1g bearing an electron-donating
methoxy group proceeded slowly, affording 3g in a moderate
yield (entry 7). The reaction of benzotriazoles having an acetyl
group on the nitrogen atom did not afford the desired product
(entry 8). The benzotriazole 1i bearing an ethoxycarbonyl group
was quickly converted to N-ethylbenzotriazole under the reac-
tion conditions (entry 9).9 The reaction of 1j having slightly
electron-donating methyl groups at the 5 and 6 positions of the
benzotriazole skeleton gave 3i in good yield (entry 10), while
that of 1k bearing strongly electron-donating methoxy groups
afforded 3j in a moderate yield along with a mixture of
unidentified products (entry 11). The reaction of 1l, which has
electron-withdrawing cyano groups at R2, did not afford the
desired product at all; decomposition of 1l was observed (entry
12). The reaction of N-unsubstituted benzotrizole with 2a did
not proceed at all. The reaction of the naphthotriazole 1m with
2a at 150 °C gave the 1H-benzo[f]indole derivative 3k in a
good yield (eq 2).
addition of the Ar-N2 bond of A to palladium(0), which
is an initial step of palladium-catalyzed cross-coupling
reaction of diazonium salts (Scheme 2).6 Herein, we report
the palladium-catalyzed denitrogenative indolization of N-
aroylbenzotriazoles 1 with disubstituted alkynes 2 to produce
the corresponding indoles 3 in good to moderate yields with
high atom efficiencies (eq 1).7
Scheme 2
.
N-Acylbenzotriazoles as Synthetic Equivalents for
2-Haloanilides
The results of the palladium-catalyzed reactions of benzotria-
zoles 1 with 6-dodecyne 2a are summarized in Table 1. The
Table 1. Palladium-Catalyzed Denitrogenative Indolization of
1-Acylbenzotriazoles 1 and 6-Dodecyne 2aa
entry
1
R1
R2
time/h
3
yieldb/%
Various alkynes were treated and results are summarized
in Table 2. The reaction of 2b, which has normal alkyl groups
1
2
3
4
5
6
7
8
1a 3,5-(F3C)2-C6H3
1b 4-F3C-C6H4
H
H
H
H
H
H
H
H
12
8
24
18
8
18
72
72
9
3a
3b
3c
3d
3e
3f
39
69
66
64
54
42
47
nr
1c
3,5-F2-C6H3
1d 4-Ac-C6H4
1e 3-F-C6H4
(4) For a review of benzotriazoles, see: (a) Katritzky, A. R.; Kirichenko,
K. ARKIVOC 2006, (iv), 119. (b) Katritzky, A. R.; Suzuki, K.; Wang, Z.
Synlett 2005, 1656. (c) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko,
O. V. Chem. ReV. 1998, 98, 409.
1f
Ph
1g 4-MeO-C6H4
1h Me
3g
(5) (a) Dimroth, O. Ann. 1909, 364, 183. (b) Katritzky, A. R.; Ji, F.-B.;
Fan, W.-Q.; Gallos, J. K.; Greenhill, J. V.; King, R. W.; Steel, P. J. J. Org.
Chem. 1992, 57, 190.
9
1i
1j
OEt
4-F3C-C6H4
H
3h
3i
3j
trace
74
41
(6) For a review, see: (a) Roglans, A.; Pla-Quintana, A.; Moreno-Man˜as,
M. Chem. ReV. 2006, 106, 4622. Recent reports: (b) Cacchi, S.; Fabrizi,
G.; Goggiamani, A.; Persiani, D. Org. Lett. 2008, 10, 1597. (c) Masllorens,
J.; Gonza´lez, I.; Roglans, A. Eur. J. Org. Chem. 2007, 158. (d) Darses, S.;
Michaud, G.; Geneˆt, J.-P. Eur. J. Org. Chem. 1999, 1875.
(7) For the concept of using a “triazole” moiety in the coupling reaction
for the synthesis of heterocycles, see: (a) Chuprakov, S.; Hwang, F. W.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757. (b) Miura, T.;
Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10, 3085. (c) Miura, T.;
Yamauchi, M.; Murakami, M. Chem. Commun. 2009, in press.
(8) The present reaction proceeded smoothly at larger scale. For example,
the reaction of 2 mmol of 1b and 3 mmol of 2a gave 3b in 69% isolated
yield.
10
11
12
Me
OMe
CN
8
11
41
1k 4-F3C-C6H4
1l 4-F3C-C6H4
c
-
a The reaction of 1 (0.25 mmol) and 2a (0.375 mmol) was carried out
in the presence of 10 mol % of Pd(PPh3)4 without solvent at 130 °C.
b Isolated yield. c Decomposition of 1l was observed.
reaction of 1-[4-(trifluoromethyl)benzoyl]benzotriazole (1b)
with 1.5 equiv of 2a in the presence of 10 mol % of Pd(PPh3)4
1056
Org. Lett., Vol. 11, No. 5, 2009

(entries 1 and 2). The reaction of 2k, which had an
electron-deficient aromatic ring at the alkynyl terminus,
with 1j led to better regioselectivity than that of 2j having
electron-rich anisyl group at R3 (entries 4 and 5). The
reaction of 1j with phenylacetylene gave a trace amount
of the desired product; phenylacetylene was quickly
decomposed under the reaction conditions (entry 6).
Further improvement of the regioselectivity is currently
ongoing in our laboratory.
Table 2. Palladium-Catalyzed Denitrogenative Indolization of 1j
and Alkynes 2a
A plausible mechanism of the present reaction is il-
lustrated in Scheme 3. Palladium(0) oxidatively inserts
entry
2
R3
3
yieldb/%
1
2
3
2b
2c
2d
2e
2f
n-Pr
3l
71
64
67
51
41
(CH2)3OAc
(CH2)3OMOM
(CH2)3OTBS
Ph
3m
3n
3o
3p
4
Scheme 3. Plausible Mechanism
5c
a The reaction of 1j (0.25 mmol) and 2 (0.375 mmol) was carried out
in the presence of 10 mol % of Pd(PPh3)4 without solvent at 130 °C for
8-9 h. All reactions were conducted in a pressure vial. b Isolated yield.
c For 41 h.
at the alkynyl moiety, with 1j proceeded smoothly (entry
1). Several protective groups of the hydroxy groups, such
as acetyl, methoxymethyl (MOM), and tert-butyldimethyl-
silyl (TBS) groups, were tolerated under the reaction
conditions (entries 2-4). Diphenylacetylene 2f reacted with
1j, affording 3p in a moderate yield (entry 5).
In the reaction of the asymmetric alkynes 2g-k, 3q-u,
in which a bulkier substituent (R3) was located at the 2
position of the indole ring, were obtained as major
products, respectively (Table 3). The alkyne 2g having a
Table 3. Palladium-Catalyzed Denitrogenative Indolization of 1j
and Unsymmetrical Alkynes 2g-la
into a C-N bond of the diazonium moiety of the 2-
iminobenzenediazonium species 4, which is thermally
generated from benzotriazole 1.4,10 Insertion of the internal
alkyne 2 into the C-Pd bond of the resulting intermediate 5
or 5′ leads to the palladacycle species 6. Reductive elimina-
tion of palladium(0) from 6 gives the product 3. Higher
reaction temperature is required for ring opening of the
triazole ring.4,5 Both the electron-withdrawing group on the
nitrogen atom and the slightly electron-donating methyl
groups at R2 play a role in stabilizing the 2-iminobenzene-
diazonium species 4 (see the Supporting Information).
Perhaps displacement of the thermodynamic equilibrium to
the intermediate 4 accelerates the desired reaction pathway
relative to decomposition of 1 under the reaction conditions.11
Presumably, alkyne insertion takes place so as to generate
steric strain in the vicinity of the shorter C-C bond rather
than the longer C-Pd bond, similar to Larock’s indole
synthesis.2b,12 Further mechanistic studies are currently
underway in our laboratory.
entry
2
R3
R4
3
yieldb/%
3:3′c
1
2g Cy
2h t-Bu
Me
Me
3q, 3q′
3r, 3r′
65
55:45
78:22
74:26
52:48
82:18
2d
3
22e
72
2i
2j
Ph
p-MeO-C6H4 n-Bu 3t, 3t′
n-Bu 3u, 3u′
3v
n-Bu 3s, 3s′
4
5
6
66
59
trace
2k p-F3C-C6H4
2l Ph
H
a The reaction of 1j (0.25 mmol) and 2 (0.375 mmol) was carried out
in the presence of 10 mol % of Pd(PPh3)4 without solvent at 130 °C for
8-9 h. All reactions were conducted in a pressure vial. b Isolated yield.
c The ratio was determined by 1H NMR spectroscopy. d For 3 days. e 20%
of 2h was recovered.
(9) Katritzky, A. R.; Zhang, G.-F.; Fan, W.-Q.; Wu, J.; Pernak, J. J.
Phys. Org. Chem. 1993, 6, 567.
(10) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bard´ıa, M.; Bonjoch, J.
J. Am. Chem. Soc. 2003, 125, 1587.
(11) When the benzotriazole 1f was heated with 1 equiv of Pd(PPh3)4
in CH3CN for 18 h, 1f decomposed.
cyclohexyl group at R3 reacted with 1j smoothly, whereas
a bulky tert-butyl group interfered with the cycloaddition
(12) Shen, M.; Li, G.; Lu, B. Z.; Hossian, A.; Roschangar, F.; Farina,
V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129
.
Org. Lett., Vol. 11, No. 5, 2009
1057

In conclusion, we are now in the position to construct
polysubstituted indole derivatives by the palladium-catalyzed
denitrogenative [3 + 2] cycloaddition of benzotriazoles and
internal alkynes under neutral conditions. The present results
suggest that benzotriazoles can be synthetic equivalents of
2-haloanilides in palladium-catalyzed reactions. Since this
reaction is free from the use of bases and the formation of
byproducts except for nitrogen gas, the present methodology
synthesizes polysubstituted indoles in an efficient and atom-
economic manner.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from Japan Society
for Promotion in Science (JSPS).
Supporting Information Available: Experimental pro-
cedures and characterization of the benzotriazoles 1 and the
products 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL900113F
1058
Org. Lett., Vol. 11, No. 5, 2009